Monday, February 11, 2019

D-glyceric aciduria

Zehavi Y, Mandel H, Eran A, Ravid S, Abu Rashid M, Jansen EEW, Wamelink MMC, Saada A, Shaag A, Elpeleg O, Spiegel R. Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review. Metab Brain Dis. 2019 Jan 12. doi: 10.1007/s311011-019-0384-x. [Epub ahead of print]

D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.

Swanson MA, Garcia SM, Spector E, Kronquist K, Creadon-Swindell G, Walter M, Christensen E, Van Hove JLK, Sass JO. d-Glyceric aciduria does not cause nonketotic hyperglycinemia: A historic co-occurrence. Mol Genet Metab. 2017 Jun;121(2):80-82.

Historically, d-glyceric aciduria was thought to cause an uncharacterized blockage to the glycine cleavage enzyme system (GCS) causing nonketotic hyperglycinemia (NKH) as a secondary phenomenon. This inference was reached based on the clinical and biochemical results from the first d-glyceric aciduria patient reported in 1974. Along with elevated glyceric acid excretion, this patient exhibited severe neurological symptoms of myoclonic epilepsy and absent development, and had elevated glycine levels and decreased glycine cleavage system enzyme activity. Mutations in the GLYCTK gene (encoding d-glycerate kinase) causing glyceric aciduria were previously noted. Since glycine changes were not observed in almost all of the subsequently reported cases of d-glyceric aciduria, this theory of NKH as a secondary syndrome of d-glyceric aciduria was revisited in this work. We showed that this historic patient harbored a homozygous missense mutation in AMT c.350C>T, p.Ser117Leu, and enzymatic assay of the expressed mutation confirmed the pathogeneity of the p.Ser117Leu mutation. We conclude that the original d-glyceric aciduria patient also had classic NKH and that this co-occurrence of two inborn errors of metabolism explains the original presentation. We conclude that no evidence remains that d-glyceric aciduria would cause NKH.

Dimer NW, Schuck PF, Streck EL, Ferreira GC. D-glyceric aciduria. An Acad Bras Cienc. 2015 Aug;87(2 Suppl):1409-14.

Inherited metabolic diseases are a heterogeneous group of diseases caused by a punctual defect in cell metabolism, resulting in the accumulation of toxic intermediate metabolites or in the lack of important biomolecules for adequate cell functioning. D-glyceric aciduria is an inherited disease caused by a deficiency of glycerate 2-kinase activity, whose pathophysiological mechanisms remain unknown. The main clinical and neurological symptoms seen in affected patients include progressive encephalopathy, hypotonia, psychomotor and mental retardation, microcephaly, seizures, speech delay, metabolic acidosis, and even death. In this review we shall discuss these clinical and biochemical findings, as well as diagnosis and treatment of affected patients in order to raise awareness about this condition.

Topcu M, Saatci I, Haliloglu G, Kesimer M, Coskun T. D-glyceric aciduria in a six-month-old boy presenting with West syndrome and autistic behaviour.Neuropediatrics. 2002 Feb;33(1):47-50.

D-Glyceric aciduria is a disease with a very heterogeneous group of symptoms, with D-glyceric acid excretion as the chief common characteristic. Findings described in previous patients include progressive neurological impairment, hypotonia, seizures, failure to thrive and metabolic acidosis. However, there are also asymptomatic patients with mild neurological impairment. A six-month-old boy was admitted to our clinic with the complaints of dullness to his environment, seizures and autistic behaviour. EEG revealed multifocal generalized epileptic activity in a hypsarrhythmia pattern. Organic acid analysis (GC-MS) in urine revealed increased glyceric acid excretion. Analysis of the optical form of glyceric acid by a polarimetric method supported the diagnosis of D-glyceric aciduria. MRI showed white matter lesions with cerebral atrophy, particularly in the frontotemporal regions, and reversible abnormalities in the mesencephalon, thalami and globus pallidium resolving after fructose restriction in the diet. To our knowledge, this is the first case report of a patient with D-glyceric aciduria who presented with West syndrome and autistic behaviour in whom serial MRI findings are also defined.

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